Heart failure is a major medical problem that affects 700 thousand individuals per year in the United States and accounts for annual costs of 10 to 40 billion dollars (Abraham and Bristow, 1997). Heart failure is the primary manifestation of dilated cardiomyopathy, a group of disorders characterized by cardiac dilation and pump dysfunction. Half of patients with dilated cardiomyopathy are diagnosed with idiopathic dilated cardiomyopathy (IDC), isolated heart failure of unknown etiology (affecting 5 to 8 in 100,000 individuals) (Manolio et al., 1992; Kasper et al., 1994). Cardiac transplantation is the only definitive treatment for end-stage disease.
IDC is hereditary in at least 20% of cases (Michels et al., 1992), indicating that genetic factors are important in its pathogenesis. In both familial and non-familial IDC, disease onset is delayed (mean age at diagnosis=45.+-.17 years) and the five-year mortality rate is 50% after symptoms develop (Michels et al., 1992; Dec and Fuster, 1994). Consequently, few multigeneration IDC families with many affected, living individuals have been identified. Although chromosomal loci for IDC (1p1-q1, 1q32, 3p22-25, 9q13-q22, 10q21-q23) have been identified by genetic linkage analysis in rare families (Mendelian Inheritance in Man, Numbers 115200, 600884, 601154, 601493, and 601494; Olson and Keating, 1997; Bowles et al., 1996), these families are too small for positional cloning of IDC genes. Furthermore, these loci do not identify all potential candidate genes, like cardiac actin (ACTC) on chromosome 15q14. As an alternative strategy, the research disclosed herein used a candidate gene approach in small IDC families.
The present invention is directed to ACTC and its gene products, mutations in the gene, the mutated gene, probes for the wild-type and mutated gene, and to a process for the diagnosis and prevention of idiopathic dilated cardiomyopathy. The instant work shows that some families with idiopathic dilated cardiomyopathy have mutations in ACTC. Idiopathic dilated cardiomyopathy is diagnosed in accordance with the present invention by analyzing the DNA sequence of the ACTC gene of an individual to be tested and comparing the respective DNA sequence to the known DNA sequence of normal ACTC. Alternatively, the ACTC gene of an individual to be tested can be screened for mutations which cause idiopathic dilated cardiomyopathy.
The publications and other materials used herein to illuminate the background of the invention or provide additional details respecting the practice, are incorporated by reference, and for convenience are respectively grouped in the appended List of References.